Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac

The serotonin 5-hydroxytryptamine (5-HT4) receptor is of potential interest for the treatment of Alzheimer’s disease because it increases memory and learning. In this study, we investigated the effect of zinc metalloprotease inhibitors on the amyloid precursor protein (APP) processing induced by the serotonin 5-HT4 receptor in vitro. We show that secretion of the non-amyloidogenic form of APP, sAPPα induced by the 5-HT4(e) receptor isoform was not due to a general boost of the constitutive secretory pathway but rather to its specific effect on α-secretase activity. Although the h5-HT4(e) receptor increased IP3 production, inhibition of PKC did not modify its effect on sAPPα secretion. In addition, we found that α secretase activity is regulated by the cAMP-regulated guanine nucleotide exchange factor, Epac and the small GTPase Rac.